The potential of proteasome inhibitors in cancer therapy

Sterz, Jan; Metzler, Ivana von; Hahne, Jens-Claus; Lamottke, Britta; Rademacher, Jessica; Heider, Ulrike; Terpos, Evangelos; Sezer, Orhan

doi:10.1517/13543784.17.6.879

Cited by 113 publications

(92 citation statements)

References 107 publications

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“…The antineoplastic effect is due to sensitization of tumor cells to apoptosis through interference with degradation of proteins implicated in cell cycle control (16) and through repression of NF-B signaling by stabilization of the cytoplasmic inhibitor I-B (16). In the myoblast cultures used in this study, Velcade concentrations that allowed us to achieve membrane repair and myoblast fusion (10 nM) were not toxic even when cells were treated for 5 days.…”

Section: Discussionmentioning

confidence: 89%

Proteasomal Inhibition Restores Biological Function of Mis-sense Mutated Dysferlin in Patient-derived Muscle Cells

Azakir

Fulvio

Kinter

et al. 2012

Journal of Biological Chemistry

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Background: Dysferlin encoded by mis-sense alleles is rapidly degraded in skeletal muscle. Results: Proteasomal inhibitors increase dysferlin levels, restore membrane repair and myotube formation in patient-derived myoblasts harboring mis-sense mutated dysferlin. Conclusion: Proteasomal inhibition restores function of mis-sense mutated dysferlin. Significance: Inhibiting the degradation of mis-sense mutated dysferlin may be a therapeutic strategy for dysferlinopathies with certain mis-sense mutations.

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Section: Discussionmentioning

confidence: 89%

Proteasomal Inhibition Restores Biological Function of Mis-sense Mutated Dysferlin in Patient-derived Muscle Cells

Azakir

Fulvio

Kinter

et al. 2012

Journal of Biological Chemistry

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“…Mutations on the b5 subunit (PSMB5) of the 20S proteasome have been associated with bortezomib resistance since it reversibly inhibits the chymotrysinlike activity of the b5 subunit of the proteasome. 28,29 As shown in Supporting Information Fig. S5, KMS20 and KMS28BM cells have possessed identical genomic DNA sequence of PSMB5 without mutation.…”

Section: Discussionmentioning

confidence: 94%

Mitochondrial modulation decreases the bortezomib-resistance in multiple myeloma cells

et al. 2013

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Multiple myeloma (MM) is an incurable hematological malignancy that causes most patients to eventually relapse and die from their disease. The 20S proteasome inhibitor bortezomib has emerged as an effective drug for MM treatment; however, intrinsic and acquired resistance to bortezomib has already been observed in MM patients. We evaluated the involvement of mitochondria in resistance to bortezomib-induced cell death in two different MM cell lines (bortezomib-resistant KMS20 cells and bortezomib-sensitive KMS28BM cells). Indices of mitochondrial function, including membrane potential, oxygen consumption rate and adenosine-5 0 -triphosphate and mitochondrial Ca 21 concentrations, were positively correlated with drug resistance of KMS cell lines. Mitochondrial genes including CYPD, SOD2 and MCU were differentially expressed in KMS cells. Thus, changes in the expression of these genes lead to changes in mitochondrial activity and in bortezomib susceptibility or resistance, and their combined effect contributes to differential sensitivity or resistance of MM cells to bortezomib. In support of this finding, coadministration of bortezomib and 2-methoxyestradiol, a SOD inhibitor, rendered KMS20 cells sensitive to apoptosis. Our results provide new insight into therapeutic modalities for MM patients. Studying mitochondrial activity and specific mitochondrial gene expression in fresh MM specimens might help predict resistance to proapoptotic chemotherapies and inform clinical decision-making.

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“…Although bortezomib is currently the only FDA-approved proteasome inhibitor, two other compounds, carfilzomib and NPI-0052, are in clinical trials (105). These two newer proteasome inhibitors are structurally distinct from bortezomib and from each other, and also exert effects that distinguish them functionally from bortezomib.…”

Section: Proteasome Inhibitorsmentioning

confidence: 99%

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

Chandra

2009

Antioxidants & Redox Signaling

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The past decade has seen an exponential increase in the number of cancer therapies with defined molecular targets. Interestingly, many of these new agents are also documented to raise levels of intracellular reactive oxygen species (ROS) in addition to inhibiting a biochemical target. In most cases, the exact link between the primary target of the drug and effects on cellular redox status is unknown. However, it is important to understand the role of oxidative stress in promoting cytotoxicity by these agents, because the design of multiregimen strategies could conceivably build on these redox alterations. Also, drug resistance mediated by antioxidant defenses could potentially be anticipated and circumvented with improved knowledge of the redoxrelated effects of these targeted agents. Given the large number of targeted chemotherapies, in this review, we focus on selected agents that have shown promise in hematologic malignancies: proteasome inhibitors, histone deacetylase inhibitors, Bcl-2-targeted agents, and a kinase inhibitor called adaphostin. Despite structural differences within classes of these compounds, a commonality of causing increased oxidative stress exists, which contributes to induction of cell death. Antioxid. Redox Signal. 11, 1123-1137.

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The potential of proteasome inhibitors in cancer therapy

Cited by 113 publications

References 107 publications

Proteasomal Inhibition Restores Biological Function of Mis-sense Mutated Dysferlin in Patient-derived Muscle Cells

Proteasomal Inhibition Restores Biological Function of Mis-sense Mutated Dysferlin in Patient-derived Muscle Cells

Mitochondrial modulation decreases the bortezomib-resistance in multiple myeloma cells

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

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